This R21 grant is designed to establish intravenous self-administration of cocaine in the mouse, with the purpose of developing a research program to investigate broader issues relating to the role functional neural-immune interactions can exert on the reinforcing efficacy of cocaine and relapse to self-administer cocaine following extinction. Advances in genetic engineering have resulted in the ability to experimentally modify discrete components of the mouse genome, allowing the study of how specific genes and/or combinations of genes influence behavioral and biological functions. This has rendered the mouse an invaluable tool for examining the reinforcing properties of drugs of abuse, and thereby aiding efforts to treat and prevent drug addiction. The molecule CD81 is an immune-related molecule, which in addition to being expressed by B lymphocytes, is also found in the brain, where it is expressed following noncontingent cocaine administration to the rat. Preliminary data has shown that the reinforcing efficacy of cocaine may be less pronounced in CD81 knockout mice, when compared to their C57BL/6 wildtype controls. Specific Aim 1 we will establish IV self-administration in the C57BL/6 mouse, using nose-poke as an operant response, and examine the secondary reinforcing properties of a tone that follows the operant response. Acquisition, maintenance and extinction parameters will be determined using different unit doses of cocaine. A second experiment will pursue this in the CD81 knockout mouse to see if rate of responding during these stages varies from the wildtype littermate controls. Based on evidence that noncontingent cocaine injections alter immune function, Specific Aim 2 will determine whether self- administration of cocaine at various unit doses (0.1-1 mg/Kg) alters the in vivo cytokine response (interleukin-1 [IL-1], IL-2, tumor necrosis factor, and interferon-gamma) to a bacterial "superantigen," staphylococcal enteroxin A (SEA). Both CD81 knockout and wildtype control animals will be examined. Finally, in Specific Aim 3, the effects of a proinflammatory cytokine (murine IL-1beta), known to activate stress circuits in the brain, will be investigated in terms of its ability to cause relapse to drug-seeking behavior as tested in (i) the conditioned place preference and (ii) intravenous self-administration paradigms. A comparison with footshock will determine whether systemic and processive stressors differ in their ability to cause relapse in the mouse. The effects of cocaine preexposure on neurobiological reactivity to IL-1beta will also be examined by measuring CRH and c- fos mRNA and plasma levels of corticosterone and ACTH. The results of these studies will be especially novel in that they may establish an important modulatory role in drug addiction and withdrawal for components involved in neural-immune interactions. This is of immediate relevance, given that drug abuse (including cocaine) is associated with high levels of infectious disease (esp. HIV).